Dakin-West Reaction

What Is the Dakin-West Reaction?

Direct conversion of an α-amino acid to the corresponding α-acetamidoalkyl methyl ketone via an oxazolone (azalactone) intermediate. The reaction is carried out in the presence of acetic anhydride and a base such as pyridine and produces CO₂. The reaction racemizes the chiral center. The Dakin-West reaction is used in the classical synthesis of strychnine, the synthesis of mimetic peptides, and other types of synthesis. Besides, the Dakin-West reaction can also be used for the synthesis of β-aryl ketones.

Mechanism of Dakin-West Reaction

The currently accepted "azlactone" pathway still follows the mechanism originally proposed by Dakin and Westand and subsequently confirmed by Allinger and coworkers. The Dakin-West reaction mechanism begins with the formation of the mixed anhydride 3 from the α-amino acid (1) or its N-acyl derivative (2). This mixed anhydride then undergoes cyclization to form the oxazolone intermediate 4. Several studies have isolated oxazolium cation 10 and mesoionic structures similar to 11, indicating their involvement in the reaction mechanism.

Deprotonation of oxazolone 4 by base results in the formation of the resonance-stabilized 1,3-oxazol-5-olate 5. The aromaticity of heterocycle 5 makes oxazolone 4 relatively acidic, facilitating deprotonation by pyridine. The anion 5 also explains the observed racemization during the reaction.

Intermediate 5 can undergo both O- and C-acylation, leading to the formation of intermediates 6a or 6b. Ring opening of these intermediates results in the mixed anhydride 7, which after transacylation leads to the α-keto acid 8. Decarboxylation of 8 ultimately yields the Dakin-West product 9.

Fig 1. Dakin-West reaction and its mechanism. [1]

Application Examples of Dakin-West Reaction

• Example 1: Brett D. Allison et al. used Dakin-West reaction to prepare trifluoromethyl acyloin via the reaction between glycolic acid and trifluoroacetic anhydride. The prepared trifluoromethyl acyloin can be further used for the scalable synthesis of β-secretase 1 (BACE 1) through a series of reactions. [2]
• Example 2: Raffael C. Wende's work first reported the development of enantioselective Dakin-West reaction, which generates α-acetylaminomethyl ketone in good yield with ee value up to 58%. The two products obtained were recrystallized once with ee value up to 84%. The key step is the enantioselective decarboxylation protonation controlled by the catalyst, which determines the asymmetric reprotonation of the intermediate enolate after decarboxylation. [3]
• Example 3: Marcus Baumann reported an effective method for diastereoselective trifluoroacetylation of highly substituted pyrrolidines by Dakin−West process. The conversion relies on a Dakin-West reaction of sophisticated pyrrolidine 2-carboxylic acid derivatives that can be constructed stereoselectively in just four synthetic steps. Significantly, this study showcases how adding side substituents to the pyrrolidine framework allows for the production of the targeted trifluoroacetylation products, a feat that was previously unattainable because trifluoromethylated oxazoles were the only products obtained. [4]

Fig 2. Synthetic examples via Dakin-West reaction.

Related Products

CAS No.	Structure	Product
6461-04-7		H-D-Glu(ome)-oh
6899-04-3		DL-Glutamine
7048-04-6		L-Cysteinehclmonohydrate
7048-04-6		H-Cys-oh.hcl
7048-04-6		L-Cysteine hydrochloride monohydrate
55516-54-6		1-Naphthalenepropanoicacid,a-amino-
3226-65-1		L-Methionine sulfoxide
18822-59-8		H-L-Tyr(tbu)-oh
70796-17-7		L-Citrullin-DL-malate
30925-07-6		L-Cystine dihydrochloride
1135695-98-5		Q-VD-OPh hydrate

References

1. Dalla-Vechia, Luciana, et al. Organic & Biomolecular Chemistry, 2012, 10(45), 9013-9020.
2. Allison, Brett D., et al. ACS omega, 2017, 2(2), 397-408.
3. Wende, Raffael C., et al. Angewandte Chemie International Edition, 2016, 55(8), 2719-2723.
4. Baumann, Marcus, et al. The Journal of Organic Chemistry, 2016, 81(23), 11898-11908.